Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response

As indicated, macrophages present a proverbial “first line of defense” against bacterial virulence, using NO as a primary weapon. Accordingly, it may seem counterintuitive that bacterial pathogens may contain their own nitric oxide synthases whose functions are to produce NO upon infection. Nevertheless, recent studies demonstrate the presence and function of NO synthases in B. subtilis

(Adak et al. 2002; Pant et al. 2002), S. aureus (Chartier and Couture 2007), and B. anthracis (Shatalin et al. 2008). Each appears to be used as a weapon in a “counterattack” to forestall macrophage-mediated bacterial cell damage and destruction. Primarily, bacterial NO may function to induce catalase activity and to diminish the Fenton reaction to diminish bacterial DNA damage as a means to prevent cytotoxicity (Gusarov and Nudler 2005; Shatalin et al. 2008). This will be considered in detail in Chapter 13.

Formation of GAPDHcys'NO by Bacterial NO Synthases

Although conventional wisdom suggests a specific role of bacterial-produced nitric oxide in catalase and Fenton reaction inhibition, the pathways described in Figure 8.3 indicate an alternative fate for that prokaryotic molecule. In particular, as GAPDH comprises approximately 10-15% of total cell protein, it is reasonable to suggest that GAPDH may provide an attractive target for bacterial produced NO. Should that be the case, bacterial produced GAPDHcys-NO could initiate pleiotropic changes in infected cells.

Support for this supposition is a previous study demonstrating oxidative stress-induced modification of active site GAPDHcys in S. aureus (Weber et al. 2004). Exposure to 100 qM H2O2 for 5 minutes resulted in a change in GAPDH pi from alkaline to acidic. Analysis of GAPDH in treated cells indicated formation of a sulfonated active site cysteine. These findings may be notable for several reasons. First, the effect is rapid in accord with the temporal sequence observed for catalase and Fenton reaction inhibition. Second, the effect is total. Only a single acidic protein species was observed. No alkaline species was detected. This total change in protein structure is in sharp contrast to the formation of small amounts of GAPDHcys-NO in eukaryotes (Benhar and Stamler 2005; Hara et al. 2005) which nevertheless results in substantial changes in eukaryotic cells. Third, the effect was reversible; within 30 minutes after H2O2 exposure bacterial proliferation is observed. En toto, this suggests the possibility that the formation of bacterial GAPDHcys-NO represents a protective measure to counter host production of nitric oxide as part of the immune response.

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